Process for the synthesis of atorvastatin form v and phenylboronates as intermediate compounds

ABSTRACT

The present invention discusses a novel process for the synthesis of [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium, atorvastatin. The compound so prepared is useful as inhibitor of the HMG-CoA reductase and may thus be used as hypolipidemic and hypocholesterolemic agent.

PRIORITY CLAIM

The present application claims the benefit under 35 U.S.C. § 371 ofInternational Application No.: PCT/IN01/00114 (published PCT applicationNo. WO 02/057274), filed 14 Jun. 2001, which claims priority toInternational Application No.: PCT/IN01/00006 (published PCT applicationNo. WO 02/057229), filed 19 Jan. 2001, the entire contents of each ofthese applications are hereby incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to a process for manufacturingR-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt, atorvastatin and novel intermediates producedduring the course of manufacture. The said compound is useful asinhibitor of the enzyme HMG-CoA reductase and is thus useful as anhypolipidemic and hypocholesterolemic agent.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,681,893, discloses a route using resolution of theracemic product using R (+) α-methyl benzyl amine. U.S. Pat. No.5,003,080 discloses a synthetic route for the preparation of the chiralform of atorvastatin. The patent discloses a process for the preparationof the lactone or its salts by coupling an ester of(4R)-6-(2-aminoethyl)-2,2-dialkyl-1,3-dioxane-3-acetate with4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutanearnidefollowed by deprotection and hydrolysis to give the product. The productsuffers from the fact that ozonolysis is required as one of the stepsfor the synthesis of the amino ketal intermediate, which is hazardousfor large scale preparation. The patent describes an alternate procedurewherein4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide isreacted with 3-amino propinaldehyde acetal followed by conventionalprocedures to give atorvastatin.

U.S. Pat. No. 5,216,174, No. 5,097,045, No. 5,103,024, No. 5,124,482,No. 5,149,837, No. 5,155,251, No. 5,245,047, No. 5,273,995, No.5,248,793, and. No. 5,397,792 describe various minor modifications inthe procedure for the preparation of atorvastatin calcium salt.

Synthesis of esters of(4R)-6-(2-aminoethyl)-2,2-dialkyl-1,3-dioxane-3-acetate is an importantpart of the preparation of atorvastatin calcium. U.S. Pat. No. 5,155,251also discloses a synthetic route for the synthesis of(3R)-4-cyano-3-hydroxy butyric acid esters from (S)-3-hydroxybutyrolactone, which in turn is synthesized from a suitable carbohydratesubstrate.

Other patents like U.S. Pat. Nos. 5,292,939, 5,319,110 and 5,374,773disclose the preparation of 3,4-dihydroxybutyric acid. However,isolation of this highly water soluble compound or its lactone is notattempted.

Another multi step procedure starting from (S)-malic acid (J. org.Chem., 1981, 46, 4319) is reported. Esters of (S)-malic acid have alsobeen used (Chem. Lett., 1984, 1389) for the synthesis of the hydroxylactone involving BMS-NaBH4 reduction, followed by lactonization. Whilea six step procedure from D-isoascorbic acid is also reported (Syn.,1987, 570) but this process requires a silica gel chromatographicseparation of the diastereomeric mixtures.

Optical resolution of the racemic hydroxylactones using lipase isdisclosed in U.S. Pat. No. 5,084,392 but this method suffers from poorenantiomeric excess and loss of the other active isomer.

Thus, the above procedures involve cumbersome reaction conditions orexpensive starting materials, reagents which are difficult to handle orhazardous for scale up, coupled with a multi step procedure whichresults in poor overall yield.

One object of the present invention is to disclose an inexpensive,simple and scalable route for the synthesis of atorvastatin. PCT pendingapplication filed on Mar. 28, 2000 (PCT/IN00/00030) discloses a processfor the synthesis but uses a different amino acid fragment for thecondensation reaction to get atorvastatin calcium.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

The process of the present invention in its first aspect is a new,improved, economical, and commercially feasible method for preparing HMGCoA reductase inhibitors of Formula XII which are useful as inhibitorsof the enzyme HMG CoA reductase and are thus useful as hypolipidemic orhypocholesterolemic agents; an embodiment of which is outlined inSchemes 1-4.

Accordingly, the present invention provides a process for the synthesisof Atorvastatin (formula XII, said process comprising steps of:

-   -   a) reacting a compound of formula X with a compound of structure        IV in a mixture of solvents selected from xylene, cyclohexane,        methyl tert-butyl ether, diisopropyl ether, and acetonitrile, in        the presence of a catalyst selected from pivalic acid,        trifluromethyl sulfonic acid, methane sulfonic acid and        p-toluene sulfonic acid, to give an intermediate of structure        XI, and    -   b) hydrolysis of the compound of structure XI followed by        calcium salt formation to get the compound of formula XII.

The compound of Formula X used in step (a) where R is selected from C₆H₅or substituted phenyls is prepared by:

-   -   a) reacting a compound of formula V with dihydro pyran to give a        protected ether of formula VI,    -   b) reacting the compound of formula VI with tert-butyl acetate        with a base at −30 to −80° C. to give a compound of formula VII,    -   c) reducing the compound of formula VII with a reducing agent to        give a compound of formula VIII,    -   d) reacting the compound of formula VIII with a protecting group        to form a protected boronate ester of formula IX, and    -   e) reducing the compound of formula IX to give a compound of        formula X.

The reducing agent used in step (c) is selected from zinc borohydride.

The protecting group used in step (d) is selected from phenyl boronicacid, tolyl boronic acid and 3-nitro benzene boronic acid.

An intermediate of formula IX, where R is selected from C₆H₅ orsubstituted phenyl.

An intermediate of formula X, where R is selected from C₆H₅ orsubstituted phenyl.

An intermediate of formula XI, where R is selected from C₆H₅ orsubstituted phenyl.

The synthetic scheme for the synthesis of the amino ester of formula Xis outlined in scheme 1.

Thus, a cyano hydroxyester of formula V is treated with dihydropyran inthe presence of p-toluenesulfonic acid in a solvent like, CH₂Cl₂, CH₃CN,DMF etc., to give the protected ether of formula VI, which issubsequently treated with the anion of tert-butyl acetate generated byreacting tert-butyl acetate with lithium diisopropylamide in THF to givea compound of formula

A β-keto ester of formula XII is then reduced using zinc borohydride inTHF to give a dihydroxy compound of formula VIII.

The dihydroxy ester compound of formula VIII is then protected using aboronic acid of formula RB(OH)₂; where R is chosen from phenyl orsubstituted phenyl to afford a boronate ester of Formula IX. Preferably,the reaction is carried out with phenyl boronic acid under a nitrogenatmosphere.

A boronate ester of Formula IX is then reduced using Raney Nickel togive the amino ester of formula X.

An amino ester of Formula X is reacted with a diketone of Formula IVwherein the process for the preparation of the compound of formula IV isdescribed in scheme 2.

A compound of formula IV is prepared as described in scheme 2, whichcomprises reacting isobutyryl chloride and meldrum's acid in thepresence of a base chosen from pyridine, triethylamine, diisopropylethylamine, dimnethylaniline etc. in CH₂Cl₂ at 0-5° C. for about 18h to givean acyl meldrum acid which is then reacted with aniline in a solventchosen from CH₂Cl₂, acetonitrile, toluene etc., at the refluxtemperature of the solvent for about 12h to afford the amide of formulaII. Preferably the reaction is done in pyridine and CH₂Cl₂ at 0C. and inCH₂Cl₂ by stirring at room temperature.

The keto amide of formula II is then reacted with benzaldehyde in thepresence of a base chosen from aqueous NaOH , or lithium hydroxide etc.,and alumina for about 26h to give the methylenephenyl intermediate offormula III.

The compound of formula III is treated with 4-fluorobenzaldehyde in thepresence of a catalyst chosen from metallic cyanide where the metal isAg, K, Na, Cu, tetraalkylammonium etc., or trimethylsilyl cyanide in apolar solvent chosen from DMSO, DMF, acetonitrile etc., at the refluxtemperature of the solvent to give a compound of formula IV. Preferablythe reaction is carried out by reacting 4-fluorobenzaldehyde and sodiumcyanide in DMSO at reflux temperature.

The diketone of formula IV is reacted with the amino ester of formula Xas described in Scheme 3 in the presence of a catalyst of FormulaR₁₂SO₃H, wherein R₁₂ is chosen from CF₃, CH₃, p-CH₃C₆H₄ and a solvent ormixtures thereof such as, for example, acetonitrile, xylene, diisopropylether cyclohexane, methyl tert-butyl ether and the like for about 24 toabout 48 hours from 5 to 10C. to about the reflux temperature of thesolvent with the removal of water to afford a compound of Formula XI.Preferably, the reaction is carried out in the presence ofmethanesulfonic acid and a mixture of xylene-hexane at reflux for about48 hours with the removal of water.

The compound of formula XI is converted to atorvastatin calcium as shownin scheme 4.

Scheme 4 involves the deprotection of the boronate ester followed byhydrolysis of the ester to give the free acid which is converted to itsammonium salt by reacting with either NH₄OH, methanolic NH₃ or bybubbling gaseous NH₃ to the solution of carboxylic acid in a solventchosen from a mixture of EtOAc, hexane, diisopropyl ether, isopropanol,cyclohexane and methanol. Preferably the intermediate of formula XI isde-protected using aqueous sodium hydroxide at room temperature over aperiod of 24h and is then hydrolyzed using methanolic sodium hydroxideand acidified using diluted HCl to give the free acid which is convertedto its ammonium salt by passing gaseous NH₃ in EtOAc. The ammonium saltis then treated with calcium acetate to give atorvastatin calcium.

The invention will now be described with reference to the followingexamples.

EXAMPLE 1

1.1 Preparation of 4-methyl-3-oxo-N-phenylpetanamide (Formula II).

To a suspension of malonic acid (104 g) in, acetic anhydride (120 mL) atroom temperature, Conc. H₂SO₄ (3 mL) was added. The mixture was cooledto 20° C. followed by the addition of acetone (8 mL) drop wise. Thecontents were stirred at room temperature (15 min) and kept at 0-5° C.overnight and filtered. The solid was washed with cold water and coldacetone and dried. The crude material was recrystallized fromacetone-hexane mixture.

Meldrum's acid (59 g) was dissolved in CH₂Cl₂ (200 mL) and cooled to 0C.Pyridine (73 mL) was added drop wise over a period of 30 min and themixture was stirred for an additional 10 min. Isobutyryl chloride (44 g)was added drop wise over a period of 30 min. and the mixture was stirredat 0° C. for 1 h followed by stirring at room temperature over night.The mixture was poured into 1.5N HCl containing crushed ice. The layerswere separated and the aqueous layer was extracted with CH₂Cl₂ (2×100mL). The combined extracts were washed with 1.5N HCl (2-100 mL) followedby saturated NH₄Cl solution (2×100 mL) and dried over Na₂SO₄ andconcentrated under reduced pressure to afford the crude acyl meldrum'sacid which was used for the next step.

The crude acyl meldrum's acid (84 g) was taken in benzene (300 mL) andaniline (111 mL) was added. The mixture was refluxed for 4h. Cool thereaction mixture to room temperature and wash with 2N HCl (5×100 mL) andbenzene was removed under reduced pressure to get formula II.

EXAMPLE 1.2

Preparation of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene) pentanamide(Formula III).

The crude amide was added to a slurry of alumina impregnated withlithium hydroxide in tetrahydrofuran. To this mixture at roomtemperature benzaldehyde was added. The contents were allowed to stirunder reflux for 2h. The contents were filtered, tetrahydrofuran wasremoved under reduced pressure and the residue was extracted withCH₂Cl₂. The organic extracts were washed with bicarbonate, bisulfitesolution, dried and concentrated under reduced pressure to afford thecrude compound of formula III.

EXAMPLE 1.3

Preparation of4-fluoro-α-[2-methyl-l-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amide(Formula IV).

To 4-fluorobenzaldehyde in anhydrous DMF, sodium cyanide was added andthe contents were refluxed for 4h. To this the intermediate from example3 was added and the contents were stirred for an additional 18h. Usualwork up affords the crude diketo compound of formula IV.

EXAMPLE 1.4

Preparation of 4-cyano-3-(O-tetrahydropyranyl) butyric acid ethyl ester(Formula VI).

A solution of 50 g of 4-cyano-3-hydroxybutyric acid ethyl ester indichloromethane (1 L) and dihydropyran (53.57 g) and catalytic quantityof PPTS (15.9 g) was stirred at room temperature over a period of 24 h.Upon completion, the contents were washed with bicarbonate, dried andsolvent was removed under reduced pressure to give the title compound.

EXAMPLE 1.5

Preparation of tert-butyl 6-cyano-5-hydroxy-3-oxobexanaote (FormulaVII).

To a solution of THF (50 mL) and diisopropylamine (37.6 ml), n-Butyllithium (186.5 ml) at a temperature of −10° C. and maintained at −3° C.for 30 min. To this solution at −20 to −25° C. tertiary butyl acetate(34.97 ml) in 35 ml of THF was added and the temperature was maintianedfor 1 h. The ether (14 g) in 14 ml of THF from the above example wasadded at −20 to −25° C. and maintained for 3 h. The contents werequenched with 3N HCl to a pH of 6-7. The organic layer was separated andthe aqueous layer was extracted with EtOAc. The combined organic layerwas washed with water, brine, dried and concentrated under reducedpressure to give the title compound of formula VII.

EXAMPLE 1.6

Preparation of tert-butyl 6-cyano-3,5-dihydroxyhexanaote (Formula VIII).

The crude product from the above example was taken up in dry THF andisopropanol under nitrogen atmosphere. The solution was cooled to −10°C. and a solution of zinc borohydride was added. The temperature wasmaintained between −10° C. to −15° C. and was allowed to warm to roomtemperature and stand for 18 h. The reaction was quenched by addition ofacetic acid and concentrated under reduced pressure to afford an oilyresidue.

EXAMPLE 1.7

Preparation of (4R)-tert-butyl 6-cyano 3,5-dibydroxy phenylboronatohexanaote (Formula IX).

To the diol from the above example (10 g) was reacted with phenylboronic acid (5.5 g) in toluene. The contents were refluxed for 20 h andthe water was collected by azeotrope distillation. Toluene was removedunder reduced pressure and petroleum ether was added to the oily residuewas cooled to 0° C. to precipitate the solid boronate.

EXAMPLE 1.8

Preparation of (4R)-tert-butyl 7-amino-3,5-dihydroxy phenylboronatoheptanoate (Formula X)

The boronate ester (5 g) from the above example was added to saturatedsolution of methanolic ammonia and Raney Nickel (5 g) was added. Thecontents were hydrogenated under pressure (5 kg). The contents werefiltered over Celite bed, methanol was removed under reduced pressure toafford the crude title compound of formula X.

EXAMPLE 1.9

Preparation of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δdibydroxy-5-(1-methylethyl)-3-phenyl-4-[phenylaminocarbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt (Formula XII)

A solution of (4R)-tert-butyl 7-amino-3,5-dihydroxy phenylboronatoheptanoate (Formula X) and4-fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutane amide(formula IV) and acetic acid in xylene were heated to reflux to 44 h.The solution was diluted with diisopropyl ether and methanol and waswashed with dilute methanolic sodium hydroxide solution, dilute HCl andthe solvent was then removed under vacuum. The crude oil was stirredwith moist silica in CH₂Cl₂ and was stirred at room temperature for 18h. A solution of aqueous NaOH was then added at room temperature and wasstirred for 4 h. The reaction mixture was diluted with water and waswashed with diisopropyl ether. The aqueous layer was acidified with HCland was taken up in diisopropyl ether. The crude acid intermediate wasthen taken up in EtOAc and NH₃ gas was bubbled. The contents werestirred for completion of the reaction and solvent was removed uponwhich the product crystallized. The crude ammonium salt is then taken upin diisopropyl ether-isopropanol mixture and a solution of calciumacetate was added at room temperature upon which the calcium saltprecipitated from the solution. The product was filtered and dried undervacuum to get formula XII of acceptable pharmaceutical purity.

The invention has been described by reference to specific embodiments,this was for the purpose of illustration only. Numerous alternativeembodiments will be apparent to those skilled in the art and areconsidered within the scope of the following claims.

1. A process for the synthesis of Atorvastatin of formula XII:

said process comprising steps of: a) reacting a compound of formula X:

 wherein R is selected from C₆H₅ or substituted phenyls;  with acompound of structure IV:

 in a mixture of solvents selected from xylene, cyclohexane, methyltert-butyl ether, diisopropyl ether, and acetonitrile, in the presenceof a catalyst selected from pivalic acid, trifluromethyl sulfonic acid,methane sulfonic acid and p-toluene sulfonic acid, to give anintermediate of structure XI:

b) hydrolysis of the compound of structure XI followed by calcium saltformation, to get the compound of formula XII.
 2. The process of claim 1wherein the compound of Formula X used in step (a) prepared by: a)reacting a compound of formula V:

 with dihydro pyran to give a protected ether of formula VI:

b) reacting the compound of formula VI with tert-butyl acetate with abase at −30 to −80° C. to give a compound off formula VII:

c) reducing a the compound of formula VII with a reducing agent to givea compound of formula VIII:

d) reacting the compound of formula VIII with a protecting group to forma protected boronate ester of formula IX:

e) reducing the compound of formula IX to give a compound of formula X.3. The process of claim 2, wherein the reducing agent used in step (c)zinc borohydride.
 4. The process of claim 2, wherein the protectinggroup used in step (d) is selected from phenyl boronic acid, tolylboronic acid and 3-nitro benzene boronic acid.
 5. An intermediate offormula IX:

where R is selected from C₆H₅ or substituted phenyls.
 6. An intermediateof formula X:

where R is selected from C₆H₅ or substituted phenyls.
 7. An intermediateof formula XI:

where R is selected from C₆H₅ or substituted phenyls.